Melatonin (N-acetyl-5-methoxytryptamine) is a naturally occurring substance that is found in animals, plants, fungi and bacteria. In humans and other mammals, melatonin is produced by the pineal gland and acts as a neurohormone, playing a key role in the maintenance of circadian rhythms. As such, it has a significant influence on many physiological functions including sleep. In this regard, it has been found that melatonin may be used in order to regularize sleep and to treat certain sleep disorders, notably insomnia.
Various clinical studies of the use of melatonin in the treatment of insomnia have been performed, and the results of some of these studies indicate that prolonged-release melatonin may indeed be effective in improving sleep latency, sleep quality and daytime alertness in adults. Other studies have also shown that melatonin administration may provide an effective treatment sleep-wake cycle disorders associated with neurodevelopmental disorders in children.
In addition to its effects on sleep, a number of additional and different health benefits have been associated with melatonin. For example, melatonin has been found, in a number of well documented studies, to have a variety of effects on inflammatory and immune processes (both as an activator and an inhibitor of these processes). In this regard, it has been found that melatonin controls the production of many different inflammatory mediators, including but not limited to leukotrienes and cytokines. In addition to specific actions on various mediator systems, melatonin may also modulate ongoing inflammatory processes by virtue of its potent antioxidant effects.
Several studies have indicated that sleep patterns are altered during inflammatory disease, and to some degree may be considered as markers of the presence and severity of the inflammatory process.
Furthermore, several different inflammatory mediator systems have been implicated in causing changes in sleep patterns. It may therefore be concluded that there is a type of inflammation-sleep interface (Clark, I. A. and Vissel, B. (2014) J. Neuroinflammation 11: 51 Inflammation-sleep interface in brain disease: TNF, insulin, orexin), and thus agents which modulate various aspects of the inflammatory process may also be capable of influencing sleep patterns and behaviour.
A very large number of different chemical mediators have been shown to be involved in the development and control of the inflammatory process. Recent studies by a number of different laboratories have implicated nitric oxide (NO) as an important modulator of a variety of acute and chronic inflammatory disorders, including various types of arthritis, gastro-intestinal diseases, inflammatory conditions of the central nervous system and certain forms of asthma. Consequently, it has been proposed that inhibition of NO production could provide a useful therapeutic mechanism for the treatment and/or management of these inflammatory disorders.
Melatonin may also play a role in several other physiological and pathological processes, and it has been suggested that adequate levels of this hormone may play a role in protecting against cardiovascular disease, various different cancers and several different degenerative conditions affecting the central nervous system.
Several plant-derived preparations have also been used to treat insomnia and other sleep disorders, with various degrees of success. These plant-derived treatments include extracts, tinctures, teas, oils or whole-plant material from inter alia the following species: valerian (Valeriana officinalis), passiflora (Passiflora incarnata), chamomile (Anthemis nobilis), Hops (Humulus lupulus), lavender (Lavandula officinalis), wild lettuce (Lactuca virosa), california poppy (Eschsholzia californica), Kava kava (Piper methysticum) and St. John's wort (Hypericum perforatum). Although various degrees of success have been reported with regard to the treatment of insomnia using these various herbal treatments, there is no consensus regarding their use, recommended dosage, standardization of the preparation used or their effectiveness in relation to other, more standard stand-alone preparations. Furthermore, many plant-derived materials (including inter alia some of those listed above) have been shown to possess anti-inflammatory activity.
Several different formulations containing melatonin for use in the treatment of insomnia are known in the art. These formulations include inter alia oral dosage forms with either immediate-release or prolonged-release characteristics (liquids, capsules or tablets), sublingual dosage forms and transdermal patches. Administration of Immediate-release dosage forms generally lead to peak blood levels being obtained within about one hour. In the case of currently-available prolonged-release formulations, peak blood levels of melatonin are reached gradually over a period of 8-10 hours, thereby mimicking the body's internal secretion profile. The sublingual route for the delivery of pharmaceutical and nutraceutical agents, whereby the active ingredients are allowed to diffuse into the bloodstream through tissues under the tongue, is well known in the art. Many different classes of pharmaceutical agents have been formulated for sublingual administration, including: cardiovascular drugs, steroids, barbiturates, enzymes, and increasingly, vitamins and minerals. Various different dosage forms may be used for sublingual delivery, including sublingual tablets (regular or fast disintegrating), lipid matrix sublingual tablets, thin films and sublingual sprays.
There are several advantages associated with drug delivery by the sublingual route, in comparison with oral administration. Firstly, the direct entry of the medicament into the blood stream (i.e. via the capillaries located in the sub-epithelial connective tissue in the floor of the mouth), often leads to a shorter onset time. In addition, the more efficient uptake of the medicament may, in some cases, permit smaller dosages to be used. However, there is a further advantage of the sublingual route that is often even more significant. This advantage relates to the fact that since sublingually administered medicaments are not absorbed through the intestinal wall into the portal circulation, they are not subject to first-pass metabolism in the liver prior to entering the general circulation. Similarly, the drugs administered by this route are protected from the hostile gastrointestinal environment and thus are not degraded by stomach acid, bile and/or enzymes such as monoamine oxidase (MAO). This is a significant advantage, in particular for active ingredients that are metabolized by MAO, such as melatonin. In summary, it may be appreciated that administration via the sublingual route may often improve the bioavailability of the medicament. Many of the advantages described hereinabove are also features of other formulations from which the active ingredient is absorbed within the oral cavity, such as buccal formulations and chewable tablets.
Despite the many advantages discussed above, many of the known sublingual delivery systems suffer from the disadvantage that the delivery performance and the bioavailability of the active ingredient are affected by its physical properties, including solubility, crystal morphology, particle size, hygroscopicity, compressibility and polarity.
One of the aims of the present invention is to provide new and improved therapeutic compositions comprising melatonin, particularly suitable for use in the treatment of insomnia and/or inflammatory conditions.
Another aim is to provide melatonin-containing compositions which provide better onset/offset times, greater efficacy and reduced undesired effects (such as excessive morning sleepiness), when compared with prior art treatments.
A still further aim of the present invention is to provide compositions comprising synergistic combinations of melatonin and certain plant extracts.
Further aims and objectives will become apparent as the description proceeds.